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Leber congenital amaurosis 9(LCA9)

MedGen UID:
325277
Concept ID:
C1837873
Disease or Syndrome
Synonyms: Amaurosis congenita of Leber, type 9; LCA 9; LCA9; LCA9 Leber Congenital Amaurosis; NMNAT1-Related Leber Congenital Amaurosis
 
Gene (location): NMNAT1 (1p36.22)
 
Monarch Initiative: MONDO:0012056
OMIM®: 608553

Definition

Early-onset neurodegeneration in the human retina can lead to Leber congenital amaurosis (LCA), the most severe human form of inherited photoreceptor-neuron degeneration resulting in congenital blindness, with an incidence of approximately 1 in 80,000 (summary by Koenekoop et al., 2012). NMNAT1 mutations have been observed to cause severe and rapidly progressive macular degeneration, leading to severe central atrophy with an appearance of congenital macular coloboma in the neonatal period, as well as an unusual early-onset atrophy of the optic nerve (Perrault et al., 2012). Some patients present with later onset and milder phenotype than typical LCA (Kumaran et al., 2021). For a general discussion of the phenotypic and genetic heterogeneity in Leber congenital amaurosis, see LCA1 (204000). [from OMIM]

Additional description

From MedlinePlus Genetics
In very rare cases, delayed development and intellectual disability have been reported in people with the features of Leber congenital amaurosis. Because of the visual loss, affected children may become isolated. Providing children with opportunities to play, hear, touch, understand and other early educational interventions may prevent developmental delays in children with Leber congenital amaurosis.

At least 20 genetic types of Leber congenital amaurosis have been described. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities.

A specific behavior called Franceschetti's oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of affected individuals poking, pressing, and rubbing their eyes with a knuckle or finger. Poking their eyes often results in the sensation of flashes of light called phosphenes. Researchers suspect that this behavior may contribute to deep-set eyes in affected children.

Leber congenital amaurosis is also associated with other vision problems, including an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). The pupils, which usually expand and contract in response to the amount of light entering the eye, do not react normally to light. Instead, they expand and contract more slowly than normal, or they may not respond to light at all.

Leber congenital amaurosis, also known as LCA, is an eye disorder that is present from birth (congenital). This condition primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. The visual impairment tends to be severe and may worsen over time.  https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis

Clinical features

From HPO
Photophobia
MedGen UID:
43220
Concept ID:
C0085636
Sign or Symptom
Excessive sensitivity to light with the sensation of discomfort or pain in the eyes due to exposure to bright light.
Eye poking
MedGen UID:
115926
Concept ID:
C0233593
Mental or Behavioral Dysfunction
Repetitive pressing, poking, and/or rubbing in the eyes.
Macular scar
MedGen UID:
140842
Concept ID:
C0423428
Acquired Abnormality
Scar tissue in the macula.
Hypermetropia
MedGen UID:
43780
Concept ID:
C0020490
Disease or Syndrome
An abnormality of refraction characterized by the ability to see objects in the distance clearly, while objects nearby appear blurry.
Keratoconus
MedGen UID:
44015
Concept ID:
C0022578
Disease or Syndrome
A cone-shaped deformity of the cornea characterized by the presence of corneal distortion secondary to thinning of the apex.
Night blindness
MedGen UID:
10349
Concept ID:
C0028077
Disease or Syndrome
Inability to see well at night or in poor light.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Color vision defect
MedGen UID:
115964
Concept ID:
C0234629
Finding
An anomaly in the ability to discriminate between or recognize colors.
Reduced visual acuity
MedGen UID:
65889
Concept ID:
C0234632
Finding
Diminished clarity of vision.
Horizontal nystagmus
MedGen UID:
124399
Concept ID:
C0271385
Disease or Syndrome
Nystagmus consisting of horizontal to-and-fro eye movements.
Macular atrophy
MedGen UID:
140841
Concept ID:
C0423421
Finding
Well-demarcated area(s) of partial or complete depigmentation in the macula, reflecting atrophy of the retinal pigment epithelium with associated retinal photoreceptor loss.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disk (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.
Bone spicule pigmentation of the retina
MedGen UID:
323029
Concept ID:
C1836926
Finding
Pigment migration into the retina in a bone-spicule configuration (resembling the nucleated cells within the lacuna of bone).
Coloboma of macula
MedGen UID:
342305
Concept ID:
C1852767
Congenital Abnormality
A congenital defect of the macula distinct from coloboma associated with optic fissure closure defects. Macular coloboma is characterized by a sharply defined, rather large defect in the central area of the fundus that is oval or round, and coarsely pigmented.
Undetectable electroretinogram
MedGen UID:
383742
Concept ID:
C1855685
Finding
Lack of any response to stimulation upon electroretinography.
Retinal pigment epithelial mottling
MedGen UID:
347513
Concept ID:
C1857644
Finding
Mottling (spots or blotches with different shades) of the retinal pigment epithelium, i.e., localized or generalized fundal pigment granularity associated with processes at the level of the retinal pigment epithelium.
Attenuation of retinal blood vessels
MedGen UID:
480605
Concept ID:
C3278975
Finding
Macular hypopigmentation
MedGen UID:
870316
Concept ID:
C4024759
Finding
Decreased amount of pigmentation in the macula lutea.
Retinal dots
MedGen UID:
1671040
Concept ID:
C4732809
Finding
Yellow, white or greyish lesions in the retina that are well-defined/distinct, individual and mostly uniform in size.
Ultra-low vision
MedGen UID:
1685679
Concept ID:
C5139143
Finding
Best corrected visual acuity worse than 1.90 logMAR (roughly 20/1590).
Ultra-low vision with retained light perception
MedGen UID:
1696045
Concept ID:
C5139243
Finding
Ultra-low vision but with retained ability to perceive the difference between light and dark.

Recent clinical studies

Etiology

Motta FL, Martin RP, Filippelli-Silva R, Salles MV, Sallum JMF
Sci Rep 2018 Oct 29;8(1):15939. doi: 10.1038/s41598-018-34380-0. PMID: 30374144Free PMC Article

Diagnosis

Motta FL, Martin RP, Filippelli-Silva R, Salles MV, Sallum JMF
Sci Rep 2018 Oct 29;8(1):15939. doi: 10.1038/s41598-018-34380-0. PMID: 30374144Free PMC Article

Clinical prediction guides

Sasaki Y, Margolin Z, Borgo B, Havranek JJ, Milbrandt J
J Biol Chem 2015 Jul 10;290(28):17228-38. Epub 2015 May 27 doi: 10.1074/jbc.M115.637850. PMID: 26018082Free PMC Article

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